title: PLU-1/JARID1B/KDM5B is required for embryonic survival and contributes to cell proliferation in the mammary gland and in ER+ breast cancer cells.
abstract: The four members of the JARID1/KDM5 family of proteins, a sub-group of the larger ARID (AT rich DNA binding domain) family, have been shown to demethylate trimethylated lysine 4 on histone 3 (H3K4me3), a chromatin mark associated with actively transcribed genes. In some lower organisms a single homologue of JARID1 is found, and functions of the four proteins found in mice and humans may be specific or overlapping. To investigate the function of the Jarid1B protein we examined the effects of deletion of the gene in mice. Systemic knock out of Jarid1b resulted in early embryonic lethality, whereas mice not expressing the related Jarid1A gene are viable and fertile. A second mouse strain expressing a Jarid1b gene with the ARID domain deleted was viable and fertile but displayed a mammary phenotype, where terminal end bud development and side branching was delayed at puberty and in early pregnancy. Since development of terminal end buds are completely dependent on signalling from the estrogen receptor (ERα), we investigated the expression of a target gene (progesterone receptor) in the ∆ARID mouse and found levels to be reduced as compared to wild-type. JARID1B is widely expressed in ER+ breast cancers and breast cancer cell lines, and interaction with ERα was demonstrated by co-immunoprecipitations in cells transfected with tagged ERα and JARID1B genes. Down-regulation of expression of JARID1B using shRNAi in MCF-7 cells resulted in a dramatic decrease in E2 stimulated tumour growth in nude mice. The data demonstrate a specific role for Jarid1B in early embryonic development, in the development and differentiation of the normal mammary gland, and in estrogen induced growth of ER+ breast cancer.
authors.affiliation: Breast Cancer Biology, King's College London, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Steven
authors.initials: S
authors.lastname: Catchpole
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: Debbie
authors.initials: D
authors.lastname: Hall
authors.forename: Samantha
authors.initials: S
authors.lastname: Santangelo
authors.forename: Ian
authors.initials: I
authors.lastname: Rosewell
authors.forename: Mounia
authors.initials: M
authors.lastname: Guenatri
authors.forename: Richard
authors.initials: R
authors.lastname: Beatson
authors.forename: Angelo G
authors.initials: AG
authors.lastname: Scibetta
authors.forename: Joy M
authors.initials: JM
authors.lastname: Burchell
authors.forename: Joyce
authors.initials: J
authors.lastname: Taylor-Papadimitriou
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000737:chemistry / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000502:physiology*; D004622:Embryo, Mammalian / Q000166:cytology* / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000032:analysis*; D005260:Female; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000502:physiology*; D008297:Male; D008321:Mammary Glands, Animal / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human; C485614:Kdm5b protein, mouse